In the modern society, people are exposed to various physical or psychosocial stresses in living environments and complicated human relations. It is known that when such stress is build up to the extent that an individual person cannot cope with, the homeostatic function of the body and mind is destroyed and an extremely wide variety of diseases thus develop, including a neurotic disorder such as depression, panic disorder, post-traumatic stress disorder and anxiety disorder; an eating disorder such as bulimia and anorexia; gastric and duodenal ulcer, irritable bowel syndrome, hypertension, ischemic heart disease, hyperventilation (hyperventilation syndrome), asthma, urticaria, alopecia areata, frequent urination, ringing in the ears and dizziness.
The hypothalamus-pituitary gland-adrenal system (HPA-axis) or the sympathetic nerve-adrenal medulla system is activated by stress stimuli. Likewise, the neuroendocrine system responds to stress.
It has been elucidated that a biological reaction to stress is controlled by stress hormones represented by corticotropin releasing hormone (CRH), neurotransmitters such as noradrenaline, serotonin and dopamine, and other various neuropeptides. Of them, CRH is a main stress hormone mediating a stress response through the HPA-axis. Clinical studies have been conducted on a CRH receptor antagonist in expectation of a therapeutic effect on various stress-related diseases; however, a sufficient therapeutic effect has not yet been observed.
A prolactin-releasing peptide (PrRP) was identified as an endogenous ligand of orphan G-protein coupled receptor, GPR10 (Nature 393 (1998) 272-276). PrRP is expressed primarily in the hypothalamus of the brain, the medulla oblongata and the intestine, and PrRP-producing nerve cells are present in the solitary nucleus of the medulla oblongatas, the ventrolateral reticular formation of the medulla oblongata and the hypothalamus. A PrRP receptor, GPR10, is present in the area postrema, the amygdala, the paraventricular nucleus and the supraoptic nucleus of hypothalamus in large amounts. Based on the nerve function of the sites at which GPR10 is expressed, it is suggested that a receptor antagonist may be useful as a therapeutic agent for various disorders including stress-related disorders (U.S. Pat. No. 6,383,764 B1). The PrRP nerve cells of the medulla oblongata are A1 and A2 noradrenaline nerve cells and it is suggested that the CRH nerve cells and oxytocin nerve cells are activated by projecting the PrRP nerve cells in the paraventricular nucleus (Neuroscience Research 38 (2000) 223-230). When PrRP is administered into the cerebral ventricle, the CRH nerve cells of the paraventricular nucleus are activated (Neuroscience Letter 285 (2000) 234-238) and release of adrenocorticotropic hormone (ACTH) and oxytocin from the pituitary gland is accelerated. Furthermore, the PrRP nerve cells of the medulla oblongata and the hypothalamus are activated by stress stimuli (Endocrinology 142 (2001) 2032-2038). These suggest that PrRP is deeply involved in the stress response of the neuroendocrine system. On the other hand, in extensive wide-genome quantitative trait loci (QTL) analysis of the obesity, dyslipemia and diabetes model rat, namely, OLETF rat (Otsuka•Long-Evans•Tokushima fatty•rat), Dmo 1 was identified as one of the gene loci significantly related to pathologic phenotypes. As a result of detailed analysis, a GPR10 gene was found. It was found that a part of the GPR10 gene was mutated in the OLETF rat and the mutation was related to obesity and dyslipemia in the obese diabetic strain rat. In order to analyze the function of the GPR10 gene, a congenic BN (Brown-Norway) rat was prepared by introducing a mutant GPR10 domain, which is defective in PrRP signal transmission, to a normal BN rat background. The mutant GPR10 congenic rat did not exhibit obesity or dyslipemia as compared to the normal BN rat, while the mutant rat expressed a resistant phenotype to stress and anxiety. The anti-stress and anti-anxiety-like behaviors of the mutant GPR10 congenic rat support involvement of the GPR10 receptor in stress response, which is estimated from the aforementioned histochemical analysis, and also supports the possibility that a GPR10 antagonist serves as a therapeutic agent for depression, anxiety disorder or various types of stress-related disorders (US 2004216177 A1, Brain Research 1178 (2007) 114-124).